Medicinal oxazolopyridine compounds

ABSTRACT

Compounds of general formula (I): ##STR1## in which: R 1  and R 2  each represent a hydrogen atom or, with the nitrogen and oxygen which bear them, form an --O--CO--N link, 
     W represents a halogen atom or a lower alkyl or alkoxy group optionally substituted with one or more halogen atoms, such as trifluoromethyl, and m being between 0 and 3, 
     A is a linear or branched alkyl radical comprising from 1 to 6 carbon atoms, 
     R 3  and R 4  are defined in the description have medicinal properties.

The present invention relates to new oxazolo[4,5-b]pyridine compounds,to a process for preparing these and to pharmaceutical compositionscontaining them.

The properties, both analgesic and anti-inflammatory, of2-phenyl-3H-oxazolo[5,4]- and -[4,5]pyridines are already known (PatentsU.S. Pat. No. 4,038,396, FR 2,328,471, FR 2,319,354, GB 1,421,619).

However, these products possess an essentially anti-inflammatoryprofile, as confirmed by the therapeutic indications mentioned in thepatents cited above, or else have the drawback of not dissociating thetwo types of activity: analogesic on the one hand, antipyretic andanti-inflammatory on the other hand.

The applicant has now discovered new compounds exhibiting a good levelof analgesic activity but possessing the especially advantageous featureof being completely devoid of anti-inflammatory activity: the compoundsof the present invention are, in effect, endowed with a high level ofpure analgesic activity. It is the case that most non-morphinicanalgesic substances known to date also posses anti-inflammatoryactivity (for example salicyl derivatives, pyrazole derivatives, etc.),and they consequently intervene in the processes occurring ininflammation. These processes involve a very large number of chemicalmediators (prostaglandins, thromboxane A2, etc.); multifariousside-effects accordingly ensue, the best known of these being attack ofthe gastric mucosa with a possibility of ulcers, and inhibition ofplatelet aggregation with disorders of coagulation. Apart from thedisturbances they cause, these concomitant effects prohibit the use ofthese products in many subjects who are especially sensitive to them.Being devoid of all anti-inflammatory activity, the compounds of thepresent invention hence do not interfere with the mediators ofinflammation, and are hence devoid of the side-effects mentioned above.This feature, combined with their complete absence of toxicity and theirhigh level of activity, renders the compounds of the present inventionusable as an analgesic much more safely and without the restrictions intheir use customarily known for the large majority of these products. Inaddition, some products of the invention have evinced an affinity formuscarine receptors, which distinguishes them completely from the priorart.

More specifically, the invention relates to compounds of general formula(I): ##STR2## in which: R₁ and R₂ each represent a hydrogen atom or,with the nitrogen and oxygen which bear them, form an --O--CO--N link,

W represents a halogen atom or a lower alkyl or alkoxy group optionallysubstituted with one or more halogen atoms, such as trifluoromethyl, andm being between 0 and 2,

A is a linear or branched alkyl radical comprising from 1 to 6 carbonatoms,

R₃ and R₄, which may be identical or different, represent;

a hydrogen atom,

a linear or branched lower alkyl group,

a linear or branched lower alkenyl group,

a cycloalkyl group having 6 to 10 carbon atoms,

an aryl or (lower alkyl)aryl or aryl(lower alkyl) group,

each of these groups being unsubstituted or substituted with one or morehalogen atoms or trifluoromethyl, hydroxyl or lower alkoxy groups, oralternatively:

R₃ and R₄, with the nitrogen atom to which they are linked, constitute asaturated or unsaturated, mono- or bicycle nitrogenous heterocyclicsystem comprising at most 12 atoms--not counting the hydrogenatoms--among which may be included one to three hetero atoms selectedfrom nitrogen, oxygen and sulfur, unsubstituted or substituted with alower alkyl or phenyl or phenyl(lower alkyl) or diphenyl(lower alkyl)group, it being possible for the phenyl, phenyl(lower alkyl) ordiphenyl(lower alkyl) groups to be substituted with one or more halogenatoms or hydroxyl, lower alkyl, lower alkoxy or trifluoromethyl groups,on condition that R₃ and R₄, with the nitrogen atom to which they arelinked, do not constitute a 4-arylpiperazine or 4-heteroarylpiperazinesystem, on the understanding that lower alkyl, lower alkenyl or loweralkyloxy radical is understood to mean a linear or branched groupcomprising from 1 to 6 carbon atoms, and that aryl or heteroaryl groupsare understood to mean unsaturated mono- or bicyclic groups comprisingfrom 5 to 12 carbon atoms--not counting the hydrogenatoms--incorporating or otherwise in their carbon skeleton one, two orthree hetero atoms selected from nitrogen, oxygen and sulfur, theirisomers, epimers and diastereoisomers, as well as their addition saltswith a pharmaceutically acceptable acid and, when R₁ and R₂ eachrepresent a hydrogen atom, their addition salts with a pharmaceuticallyacceptable base.

Among acids which may be added to the compounds of formula (I) to forman addition salt, hydrochloric, sulfuric, phosphoric, tartaric, malic,maleic, fumaric, oxalic, methanesulfonic, ethanesulfonic, camphoric,citric, etc., acids may be mentioned by way of example.

Among bases which may be added to the compounds of formula (I) for whichR₁ and R₂ each represent a hydrogen atom, alkali metal hydroxides,alkali metal salts, etc., may be mentioned by way of example.

The invention also encompasses the process for obtaining compounds offormula (I), wherein a compound of formula (II): ##STR3## in which W, mand A have the same meaning as in the formula (I) and X represents ahalogen atom, is reacted, preferably under an inert atmosphere, with acompound of formula (III), preferably in excess: ##STR4## in which R₃and R₄ have the same meaning as in the formula (I), in an organic mediumin the presence of a basic agent and at a temperature between roomtemperature and the refluxing temperature of the chosen solvent, tolead, after cooling, extraction and, where appropriate, purification, toa compound of formula (I/A): ##STR5## a special case of the compounds offormula (I) for which R₁ with R₂ forms a C═O group, which may, if sodesired, be separated, where applicable, into its isomers and thensalified with a pharmaceutically acceptable acid, which compound offormula (I/A) may be treated, if so desired, with an alkaline agent inaqueous solution, at a temperature between room temperature and theboiling point of the reaction medium, to lead, where appropriate afteracidification and/or neutralization of the reaction medium, to acompound of formula (I/B): ##STR6## a special case of the compounds offormula (I) in which R₁ and R₂ each represent a hydrogen atom and W, m,A, R₃ and R₄ have the same meaning as above, which is purified, ifnecessary, by a technique selected from crystallization andchromatography and which is salified, if so desired, with apharmaceutically acceptable acid or base.

The compounds of formula (II) may be obtained by reacting a compound offormula (IV): ##STR7## in which W and m have the same meaning as in theformula (I), with an alkali metal hydroxide in an aqueous medium or analkali metal alcoholate in an organic medium, to lead to a derivative offormula (V): ##STR8## in which W and m have the same meaning as aboveand L represents an alkali metal, which is condensed with a compound offormula (VI):

    X--A--X'                                                   (VI)

in which A has the same meaning as above and X and D', which may beidentical or different, each represent a halogen atom, preferably underan inert atmosphere, in an organic medium at a temperature between roomtemperature and the refluxing temperature of the chosen solvent, tolead, after, where appropriate, extraction and purification bychromatography and/or crystallization, to the compound of formula (II).

The compounds of formula (I/A) may also be obtained by condensation of acompound of formula (V) as shown above with a compound of formula (VII):##STR9## in which X, A, R₃ and R₄ have the same meaning as above, in anorganic medium at a temperature between room temperature and therefluxing temperature of the chosen solvent, to lead, after, whereappropriate, cooling, extraction and purification, to a compound offormula (I/A) as defined above, the isomers of which, where applicable,are separated and which is salified, if so desired, with apharmaceutically acceptable acid.

The compounds of formula (VII) will advantageously be obtained bycondensation of a compound of formula (VI) as defined above with anamine of formula (III) as defined above, preferably under an inertatmosphere, in an organic medium at a temperature between roomtemperature and the refluxing temperature of the chosen solvent, tolead, after, where appropriate, extraction and purification, to acompound of formula (VII).

A special case of the compounds of the present invention consists of thecompounds of formula (I) in which A is a methylene link --CH₂ --.

These compounds will advantageously be obtained in a single step bydissolving a compound of formula (IV), a slight excess of an amine offormula (III) and an excess of formaldehyde in a lower aliphatic alcoholmedium, and heating the solution thereby obtained to a temperaturebetween room temperature and the boiling point of the solution, to lead,after, where appropriate, cooling, allowing the mixture to stand for oneto two hours, filtration and, where appropriate, chromatography on asilica column, to a compound of formula (I/A1): ##STR10## a special caseof the compounds of formula (I/A) in which A is a methylene link --CH₂-- and in which W and m have the same meaning as in the formula l(I),which may be salified, if so desired, with a pharmaceutically acceptableacid and converted, if so desired, to a compound (I/B1): ##STR11## aspecial case of the compound of formula (I/B) in which A is a methylenelink CH₂ and W and m have the same meaning as in the formula (I), bytreatment of a compound of formula (I/A1) with an alkaline agent inaqueous solution as described for the conversion of the compounds offormula (I/A) to a compound of formula (I/B).

The compounds of formula (I) possess advantageous pharmacologicalproperties.

In particular, these compounds have evinced advantageous analgesicactivity.

A pharmacological study of the compounds of the invention showed thatthey were of low toxicity, endowed with a high level of pure analgesicactivity, devoid of an anti-inflammatory component and hence devoid ofdrawbacks inherent in most compounds exhibiting this activity(ulcerogenic action on the mucosi, interference with coagulation, etc.).This spectrum of activity hence renders the compounds of the presentinvention especially advantageous in a number of indications such asrheumatic pain such as that associated with sprains, fractures anddislocations, post-traumatic pain, postoperative pain, dental pain,neurological pain such as facial neuralgia, visceral pain such asnephritic colic, dysmenorrhea, proctological surgery, pancreatitis,diverse pains, headache, cancer pain, etc.

In addition, the compounds of the invention have evinced a good affinityfor MI receptors. This means that they may be used profitably indisorders of cerebral circulatory insufficiency, the multifariousdisorders resulting from normal or pathological aging, memory loss andAlzheimer's disease.

The subject of the present invention is also pharmaceutical compositionscontaining the products of formula (I) or one of their addition saltswith a pharmaceutically acceptable acid, alone or in combination withone or more pharmaceutically acceptable, non-toxic, inert excipients orvehicles.

Among the pharmaceutical compositions according to the invention, theremay be mentioned, more especially, those which are suitable for oral,parenteral, nasal, rectal, perlingual, ocular or respiratoryadministration, and in particular injections, aerosols, eye or nasaldrops, simple or sugar-coated tablets, sublingual tablets, sachets,packets, hard gelatin capsules, sublingual preparations, troches,suppositories, creams, ointments, skin gels, and the like.

The appropriate dosage varies according to the patient's age and weight,the administration route and the nature of the therapeutic indicationand of any associated treatments, and ranges between 1 centigram and 4grams per 24 hours.

The examples which follow illustrate the invention and in no way limitit.

The ¹ H nuclear magnetic resonance spectra were recorded using TMS as aninternal reference. The infrared spectra were recorded using a KBr diskcontaining approximately 1% of the test product.

The products obtained according to the procedures described under theheading "Preparations" do not form part of the invention; theynevertheless constitute synthesis intermediates useful for thepreparation of the compounds of the invention.

PREPARATIONS Preparation 1: 3H-Oxazolo[4,5-b]pyridin-2-one* (SeeAppendix)

5.5 g (0.05 mol) of 2-amino-3-hydroxypyridine are introduced into athree-necked flask and the system is placed under argon. 100 ml ofanhydrous tetrahydrofuran (THF) are added. 12.15 g (0.075 mol) of1,1-carbonyldiimidazole are then introduced. The mixture is heated toreflux for 5 hours (under argon). The THF is then evaporated off. Theresidue is taken up with dichloromethane. Washes of the organic phaseare performed with NaOH solution (5%) (6×150 ml); the cyclized productpasses into the aqueous phase and is precipitated at a pH in the regionof 5 (by adding 2N hydrochloric acid solution). The product is filteredoff and stored in a desiccator.

Yield: 77%

Melting point: 212°-214° C.

Preparation 2:5-Methyl-3H-Oxazolo[4,5-b]Pyridin-2-One* (See Appendix)Stage A: 2-Nitro-3-Hydroxy-6-Methylpyridine

5.45 g (50 mmol) of 5-hydroxy-2-methylpyridine are added to 20 ml ofconcentrated sulfuric acid while cooling in an ice bath. The temperatureis maintained at +6° C. and 2.35 ml of fuming nitric acid are added withstirring. The mixture is left overnight at room temperature. 100 g ofice are added with stirring. The product is filtered off, rinsed withwater and dried.

Stage B: 2-Amino-3-Hydroxy-6- Methylpyridine

3.5 g of 2-nitro-3-hydroxy-6-methylpyridine are placed under a hydrogenpressure in 50 ml of methanol in the presence of 1 gram of palladinizedcharcoal. The mixture is stirred and filtered. The methanol isevaporated off.

Stage C: 5-Methyl-3H-Oxazolo[4,5-b]Pyridin-2-One

1.24 g (10 mmol) of 2-amino-3-hydroxy-6-methylpyridine are introducedinto a three-necked round-bottomed flask. The contents are placed underargon. 20 ml of anhydrous tetrahydrofuran and then 2.43 g (15 mmol) of1,1-carbonyldiimidazole are added. The mixture is heated to reflux for 6hours. The reaction medium is evaporated. The crystals obtained arewashed with water, filtered off and redissolved in hot methanol. Thesolution is filtered and re-evaporated.

Yield: 75%

Melting point: 243° C.

Spectral characteristics:

¹ H NMR Solvent CDCl₃ : δ ppm δ: 12.3 1H, unresolved complex, NH δ: 7.51H; doublet; H₇ ; J=8 Hz δ: 6.9 1H; doublet: H₆ ; J=8 Hz δ: 2.4 3H;singlet; CH₃

Infrared: 1750 cm⁻¹, ν (C═O) 1610 cm⁻¹, ν (C═C)

Preparation 3: 3-(2-Bromoethyl)-3H-Oxazolo[4,5-b]Pyridin-3-One Stage A:Oxazolo[4,5-b]Pyridin-2-One Sodium Derivative

6 g (44.11 mmol) of 3H-oxazolo[4,5-b]pyridin-2-one are dissolved in asufficient quantity of tetrahydrofuran, and this solution is then addedto an ethanolic solution of sodium ethylate obtained from 1 gram (43.50mmol) of sodium in approximately 150 ml of ethanol. The mixture isevaporated under vacuum and the residue is taken up with a sufficientquantity of dimethylformamide to dissolve it.

Stage B: 3-(2-Bromoethyl)-3H-Oxazolo[4,5-b]Pyridin-2-One

7.6 ml (88.22 mmol) of 1,2-dibromoethane, dissolved in approximately 50ml of dimethylformamide, are placed in a round-bottomed flask underargon, surmounted by a condenser, and the solution obtained in thepreceding step is then added slowly with stirring. The mixture isbrought to 100° C. for 2 hours.

After cooling, the dimethylformamide is evaporated under vacuum and theresidue is then taken up with water and extracted with methylenechloride. After drying over MgSO₄, the methylene chloride is evaporatedoff and the residue is purified on a flash silica column (230-240 mesh)in methylene chloride. After evaporation, 5.2 g of a white powder areobtained.

Yield: 50%

Preparation 4: 3-(3-Bromopropyl)-3H-Oxazolo[4,5-b]Pyridin-2-One

Using the procedure described in Preparation 3, but replacing1,2-dibromoethane in stage B by 1,3-dibromopropane, the product of thetitle is obtained.

Preparation 5: 3-(4-Bromo-n-Butyl)-3H-Oxazolo[4,5-b]Pyridin-2-One

Using the procedure described in Preparation 3, but replacing1,2-dibromoethane in stage B by 1,4-dibromo-n-butane, the product of thetitle is obtained.

Yield: 50%

Melting point: 46° C.

Spectral characteristics:

¹ NMR Solvent CDCl₃ : δ ppm δ: 1.92-2.09 ppm, multiplet; 4H; --CH₂ --CH₂--CH₂ --CH₂ --Br δ: 3.47 ppm; triplet; 2H; CH₂ --Br δ: 3.99 ppm;triplet; 2H δ: 7.06 ppm; doublet of doublet; 1H; H₆ ; JH₆ H₇ =8.3 Hz JH₆H₆ =6.4 Hz δ: 7.40 ppm; doublet of doublet; 1H; H₇ ; JH₇ H₆ =8.3 Hz JH₇H₅ =1 Hz δ: 8.11 ppm; doublet of doublet; 1H; H₅ ; JH₅ H₆ =5.3 Hz JH₅ H₇=1 Hz

Preparation 6: 5-Methyl-3-(2-Bromoethyl)-3H-Oxazolo[4,5-b]Pyridin-2-One

Using the procedure described in Preparation 3, but replacing3H-oxazolo[4,5-b]pyridin-2-one by5-methyl-3H-oxazolo[4,5-b]pyridin-2-one, the product of the title isobtained.

EXAMPLE 1: 3-(2-PIPERIDINOETHYL)-3H-OXAZOLO[4,5-b]PYRIDIN-2-ONE

0.01 mol of 3-(2-bromoethyl)-3H-oxazolo[4,5-b]pyridin-2-one, dissolvedin acetonitrile, 0.15 mol of piperidine and 0.015 mol ofdiisopropylethylamine are introduced into a round-bottomed flask placedunder argon and surmounted by a condenser. The mixture is brought to 80°C. for 12 hours. It is cooled, the acetonitrile is evaporated off undervacuum and the residue is taken up with water. The alkalinity of themedium is checked and the medium is extracted with dichloromethane. Theorganic phase is dried over magnesium sulfate and evaporated and theresidue is recrystallized.

Yield: 97%

Melting point: 84° C.

Spectral characteristics:

Infrared: 3100-2700 cm⁻¹, ν (CH) 1760 cm⁻¹, ν (C═O) 1590 cm⁻¹, ν (C═C)conjugated

Nuclear magnetic resonance:

¹ H NMR Solvent CDCl₃ : δ ppm δ: 1.34-1.56, 6H; multiplet; piperidine (βand γ to the nitrogen) δ: 2.42-2.55, 4H; multiplet; piperidine (α to thenitrogen) δ: 2.76, 2H; triplet; piperidine CH₂ --CH₂ ; J=4.1 Hz δ: 4.07,2H; triplet; CH₂ --CH₂ ; piperidine; J=6.1 Hz δ: 7.03 ppm: 1H; doubletof doublet; aromatic; H₆ δ: 8.09 ppm: 1H; doublet of doublet; aromatic;H₅

EXAMPLE 2:3-[2-(4-METHYL-1-PIPERAZINYL)ETHYL]-3H-OXAZOLO[4,5-b]PYRIDIN-2-ONE

Using the procedure described in Example 1, but replacing piperidine by1-methylpiperazine, the product of the title is obtained.

Yield: 90%

Melting point: 85° C.

Spectral characteristics:

Infrared: 3100-2700 cm⁻¹, ν (CH) 1760 cm⁻¹, ν (C═O) 1590 cm⁻¹, ν (C═C)conjugated

Nuclear magnetic resonance:

¹ H NMR Solvent CDCl₃ : δ ppm δ: 2.23, singlet; 3H; CH₃ δ: 2.25-2.70,multiplet; 8H; piperazine δ: 2.79, 2H; triplet; piperazine CH₂ --CH₂ δ:4.05, 2H; triplet; piperazine CH₂ --CH₂ δ: 7.04: 1H; doublet of doublet;aromatic; H₆ δ: 7.39: 1H; doublet of doublet; aromatic; H₇ δ: 8.09 1H;doublet of doublet; aromatic; H₅

EXAMPLE 3: 3-[2-(1-PYRROLIDINYL)ETHYL]-3H-OXAZOLO[4,5-b]PYRIDIN-2-ONE(OXALATE)

Using the procedure described in Example 1, but replacing piperidine bypyrrolidine, the product of the title is obtained in the form of a base.The product is dissolved in ethanol and 0.01 mol of oxalic acid isadded. The product is drained.

Melting point: 180° C.

Spectral characteristics:

Infrared: 3100-2700 cm⁻¹, ν (CH) 1760 cm⁻¹, ν (C═O) 1590 cm⁻¹, ν (C═C)

Nuclear magnetic resonance:

¹ H NMR Solvent CDCl₃ : δ ppm δ: 7.04: 1H; doublet of doublet; aromatic;H₆ δ: 7.39: 1H; doublet of doublet; aromatic; H₇ δ: 8.09 1H; doublet ofdoublet; aromatic; H₅

EXAMPLE 4: 3-(2-MORPHOLINOETHYL]-3H-OXAZOLO[4,5-b]PYRIDIN-2-ONE

Using the procedure described in Example 1, but replacing piperidine bymorpholine, the product of the title is obtained.

Yield: 98%

Melting point: 83° C.

Spectral characteristics:

Infrared: 3100-2700 cm⁻¹, ν (CH) 1760 cm⁻¹, ν (C═O) 1590 cm⁻¹, ν (C═C)

Nuclear magnetic resonance:

¹ H NMR Solvent CDCl₃ : δ ppm δ: 2.49-2.53: 4H; multiplet; 2 CH₂ α tothe nitrogen:morpholine δ: 2.68: 2H; CH₂ --CH₂ --morpholine; J=6.3 Hz δ:3.54-3.58: 4H; multiplet; 2CH₂ α to the oxygen; morpholine δ: 4.04: 2H;triplet; CH₂ --morpholine; J=6.3 Hz δ: 7.03: 1H; doublet of doublet;aromatic; H₆ δ: 7.38: 1H; doublet of doublet; aromatic; H₇ δ: 8.08: 1H;doublet of doublet; aromatic; H₅

EXAMPLE 5: 3-(2-AMINOETHYL)-3H-OXAZOLO[4,5-b]PYRIDIN-2-ONE(HYDROCHLORIDE)

0.013 mol of hexamethylenetetramine, dissolved beforehand in 20 cm³ ofchloroform, and 0.01 mol of3-(2-bromoethyl)-3H-oxazolo[4,5-b]pyridin-2-one, dissolved beforehand in15 cm³ of chloroform, are introduced into a round-bottomed flask placedunder argon and surmounted by a condenser. The mixture is heated toreflux for one week. The product is drained and dried. The precipitateis introduced into a ground-necked 250-cm³ flask equipped with a refluxcondenser, and 50 cm³ of absolute alcohol and 10 cm³ of concentratedhydrochloric acid are added. The mixture is heated to reflux for twohours with magnetic stirring. The solvent is evaporated off on a waterbath under vacuum and the product is recrystallized in alcohol at 95° C.

Yield: 70%

Spectral characteristics:

Infrared: 3200-2400 cm⁻¹, ν (NH) and ν (CH)

Nuclear magnetic resonance:

¹ H NMR Solvent CDCl₃ : δ ppm δ: 7.05 ppm: 1H; aromatic; H₆ δ: 7.38 ppm:1H; aromatic; H₇ δ: 8.09 ppm: 1H; aromatic; H₅

EXAMPLE 6:3-[2-(N-METHYL-N-BENZYLAMINO)ETHYL]-3H-OXAZOLO[4,5-b]PYRIDIN-2-ONE

Using the procedure described in Example 1, but replacing piperidine byN-methyl-N-benzylamine, the product of the title is obtained.

Yield: 75%

Spectral characteristics:

Infrared: 3100-2700 cm⁻¹, ν (CH) 1760 cm⁻¹, ν (C═O)

Nuclear magnetic resonance:

¹ H NMR Solvent CDCl₃ : δ ppm δ: 2.20 ppm, singlet: 3H; CH₃ δ: 7.03 ppm:1H; H₆ δ: 7.38 ppm: 1H; H₇ δ: 8.09 ppm: 1H; H₅ δ: 7.27 ppm: 5H; aromatic(C₆ H₅ --CH₂)

EXAMPLE 7: 3-[2-(METHYLAMINO)ETHYL]-3H-OXAZOLO[4,5-b]PYRIDIN-2-ONE

In a 1,000-cm³ ground-necked flask, 0.02 mol of3-[2-(N-methyl-N-benzylamino)ethyl]-3H-oxazolo[4,5-b]pyridin-2-one isdissolved in 250 cm³ of methanol. 0.2 g of palladinized charcoal isintroduced and the mixture is stirred under a hydrogen atmosphere atroom temperature and atmospheric pressure. After absorption of thetheoretical quantity of hydrogen, the reaction medium is filtered. Thefiltrate is concentrated on a water bath under vacuum and acidified witha stream of gaseous hydrochloric acid. The precipitate obtained isdrained, dried and recrystallized.

Yield: 75%

Spectral characteristics:

Infrared: 3100-2600 cm⁻¹, ν (NH) or ν (CH) 2440 cm⁻¹, ν (NH) 1750 cm⁻¹,ν CO (OCON) 1610 cm⁻¹, ν (C═C) aromatic

Nuclear magnetic resonance:

¹ H NMR Solvent CDCl₃ : δ ppm δ: 7.05 ppm, doublet of doublet; 1H; H₆ δ:7.38 ppm; doublet of doublet; 1H; H₇ δ: 8.09 ppm, doublet of doublet;1H; H₅

EXAMPLE 8: 3-[2-(ISOPROPYLAMINO)ETHYL]-3H-OXAZOLO[4,5-b]PYRIDIN-2-ONE(HYDROBROMIDE)

0.1 mol of isopropylamine and 0.01 mol of3-(2-bromoethyl)-3H-oxazolo[4,5-b]pyridin-2-one, dissolved beforehand in40 cm³ of acetonitrile, are introduced into a 100-cm³ ground-neckedround-bottomed flask equipped with a reflux condenser. The mixture isheated to reflux for 15 hours. After cooling, the precipitate obtainedis drained, dried and recrystallized.

Yield: 92%

Spectral charcteristics:

Infrared: 3100-2650 cm⁻¹, ν (NH) and ν (CH) 2450 cm⁻¹, ν (NH) 1745 cm⁻¹,ν CO

EXAMPLE 9: 3-[2-(CYCLOPROPYLAMINO)ETHYL]-3H-OXAZOLO[4,5-b]PYRIDIN-2-ONE(HYDROBROMIDE)

Using the procedure described in Example 8, but replacing isopropylamineby cyclopropylamine, the product of the title is obtained.

EXAMPLE 10: 3-[2-(DIETHYLAMINO)ETHYL]-3H-OXAZOLO4,5-b]PYRIDIN-2-ONE(OXALATE)

Using the procedure described in Example 1, but replacing piperidine bydiethylamine, the product of the title is obtained in the form of abase. It is dissolved in ethanol and 0.01 mol of oxalic acid is added.The product is drained. It is dried. It is recrystallized.

Melting point: 139° C.

EXAMPLE 11:3-[2-(N-METHYL-N-CYCLOHEXYLAMINO)ETHYL]-3H-OXAZOLO[4,5-b]PYRIDIN-2-ONE

Using the procedure described in Example 1, but replacing piperidine byN-methyl-N-cyclohexylamine, the product of the title is obtained.

EXAMPLE 12:3-[2-(4-PHENYLPIPERIDINO)ETHYL]-3H-OXAZOLO[4,5-b]PYRIDIN-2-ONE

Using the procedure described in Example 1, but replacing piperidine by4-phenylpiperidine, the product of the title is obtained.

Melting point: 88° C.

EXAMPLE 13:3-[2-(1,2,3,4-TETRAHYDRO-1-QUINOLYL)ETHYL]-3H-OXAZOLO[4,5-b]PYRIDIN-2-ONE

Using the procedure described in Example 1, but replacing piperidine by1,2,3,4-tetrahydroquinoline, the product of the title is obtained.

EXAMPLE 14: 3-MORPHOLINOMETHYL-3H-OXAZOLO[4,5-b]PYRIDIN-2-ONE

4.1 g (0.03 mol) of 3H-oxazolo[4,5-b]pyridin-2-one are dissolved in 100ml of alcohol at 95° C. 2.88 g (0.33 mol) of morpholine and then 3 ml of30% aqueous formaldehyde solution are added. The mixture is stirred on awater bath at a temperature in the region of 50° C. for one hour 30minutes, stirring being maintained. The mixture is left to stand for onehour at room temperature. The crystals are drained and recrystallized.

Yield: 85%

Spectral characteristics:

Infrared: 3100-2700 cm⁻¹, ν (CH) 1760 cm⁻¹, ν (CO) 1590 cm⁻¹, ν (C═C)

EXAMPLE 15: 3-(1-PYRROLIDINYLMETHYL)-3H-OXAZOLO[4,5-b]PYRIDIN-2-ONE

Using the procedure described in Example 14, but replacing morpholine bypyrrolidine, the product of the title is obtained.

EXAMPLE 16: 3-PIPERIDINOMETHYL-3H-OXAZOLO[4,5-b]PYRIDIN-2-ONE

Using the procedure described in Example 14, but replacing morpholine bypiperidine, the product of the title is obtained.

EXAMPLE 17:3-(2-PIPERIDINOETHYL)-5-METHYL-3H-OXAZOLO[4,5-b]PYRIDINE-2-ONE

Using the procedure described in Example 1, but replacing3-(2-bromoethyl)-3H-oxazolo[4,5-b]pyridin-2-one by3-(2-bromoethyl)-5-methyl-3H-oxazolo[4,5-b]pyridin-2-one obtained inPreparation 6, the product of the title is obtained.

EXAMPLE 18:3-[2-(4-TRIFLUOROMETHYLBENZYLAMINO)ETHYL]-3H-OXAZOLO[4,5-b]PYRIDIN-2-ONE

Using the procedure described in Example 1, but replacing piperidine by4-trifluoromethylbenzylamine, the product of the title is obtained.

EXAMPLE 19:3-[2-(4-METHYLPIPERIDINO)ETHYL]-3H-OXAZOLO[4,5-b]PYRIDIN-2-ONE

Using the procedure described in Example 1, but replacing piperidine by4-methylpiperidine, the product of the title is obtained.

EXAMPLE 20:3-[2-(4-BENZYLPIPERIDINO)ETHYL]-3H-OXAZOLO[4,5-b]PYRIDIN-2-ONE

Using the procedure described in Example 1, but replacing piperidine by4-benzylpiperidine, the product of the title is obtained.

EXAMPLE 21:3-[2-(2-CHLOROETHYLAMINO)ETHYL]-3H-OXAZOLO[4,5-b]PYRIDIN-2-ONE

Using the procedure described in Example 1, but replacing piperidine by2-chloroethylamine, the product of the title is obtained.

EXAMPLE 22:3-{2-[4-(4,4'-DIFLUOROBENZHYDRYL)-1-PIPERAZINYL]ETHYL}-3H-OXAZOLO[4,5-b]PYRIDIN-2-ONE

Using the procedure described in Example 1, but replacing piperidine by1-(4,4'-difluorobenzhydryl)piperazine, the product of the title isobtained.

EXAMPLE 23:3-[2-(4-BENZHYDRYL-1-PIPERAZINYL)ETHYL]-3H-OXAZOLO[4,5-b]PYRIDIN-2-ONE

Using the procedure described in Example 1, but replacing piperidine by1-benzhydrylpiperzine, the product of the title is obtained.

EXAMPLE 24:3-{2-[4-(4-CHLOROBENZHYDRYL)-1-PIPERAZINYL]ETHYL}-3H-OXAZOLO[4,5-b]PYRIDIN-2-ONE

Using the procedure described in Example 1, but replacing piperidine by1-(4-chlorobenzhydryl)piperazine,

EXAMPLE 25: 2-(2-PIPERIDINOETHYLAMINO)-3-PYRIDINOL

0.01 mol of 3-(2-piperidinoethyl)-3H-oxazolo[4,5-b]pyridin-2-one,obtained in Example 1, is placed in 50 ml of 10% sodium hydroxidesolution. The mixture is heated to reflux for 4 hours with magneticstirring. After cooling, the solution is acidified with 30% hydrochloricacid. While cooling, saturated aqueous sodium bicarbonate solution isadded until the pH=7. The precipitate is filtered off and washed threetimes with water, dried under vacuum in a desiccator and then washedagain.

By using the procedure described in Example 25, but employing thecompounds obtained in Examples 2 to 24 as starting material,2-{[(substituted)amino]alkylamino}-3-pyridinols, substituted whereappropriate, are obtained.

PHARMACOLOGICAL STUDY OF THE COMPOUNDS OF THE INVENTION EXAMPLE 26:STUDY OF THE ACUTE TOXICITY

The toxicity was assessed after oral administration of increasing doses(0.1, 0.25, 0.50, 0.75 and 1 g/kg) to batches of five mice (20±2 grams).The animals were observed at regular intervals during the first day, anddaily during the two weeks following the treatment.

It is apparent that the compounds of the invention are completelynon-toxic.

EXAMPLE 27: STUDY OF THE ANALGESIC ACTIVITY

The activity against pain was investigated in mice (23-25 g) accordingto a protocol derived from the technique described by SIEGMUND (SIEGMUNDE. A., R. A. CADMUS & GOLU, J. Pharm. Exp. Ther. 119, 184, 1957). Themice, randomized in batches of 12 animals, received the treatment orally(excipient for the controls) 1 hour before the intraperitoneal injectionof a 0.02% aqueous-alcoholic solution of phenyl-p-benzoquinone. Thewrithing movements are counted between the 5th and 10th minute afterinjection.

The percentage activity obtained was evaluated for each dose (% decreasein the number of writhing movements in the treated animals relative tothe controls). An ED₅₀, the dose producing a 50% activity, wasdetermined for each product tested.

EXAMPLE 28: STUDY OF THE ANTI-INFLAMMATORY ACTIVITY

The anti-inflammatory potential of the compounds was investigated on amodel of acute inflammation induced by the subcutaneous injection of asolution of carrageenan into the rat hind foot, according to a techniquebased on the method of WINTER, C. A., E. A. RISLEY and G. N. NUSS--Proc.Soc. Exp. Med. 111, 554, 1962. The rats (100-120 g), randomized inbatches of 8, were treated (including the controls, which receiveexcipient) 1 hour before the local injection of a 0.5% suspension ofcarrageenan (Sigma type IV; 0.1 ml per rat). The edema is determined 3hours after injection, by plethysmometric measurement (UGO BASILE waterplethysmometer) of the volume of each of the hind feet (edema=volume ofthe inflamed foot--volume of the non-inflamed foot).

The percentage activity corresponds to the percentage decrease in themean edema of the batch compared to the mean of the correspondingcontrol batch. An ED₃₀, the dose producing a 30% activity, wasdetermined.

This ED₃₀ is equal to 50 mg.kg⁻¹ for the compound of Example 6 of U.S.Pat. No. 4,038,396. It is very markedly greater than this value for allthe compounds of the invention; up to a dose of 150 mg/kg⁻¹, they haveno anti-inflammatory activity.

EXAMPLE 29: GASTRIC TOLERANCE TEST

A group of 5 rats is subjected to fasting for 24 hours. The testproducts are administered orally, in suspension in acacia syrup at adose of 150 mg.kg⁻¹. After administration, the animals are placed underso-called semi-constrained conditions reputed to be ulcerogenic (theyare shut up in narrow cages. After 6 hours, they are sacrificed and thestomach wall is examined. Gastric tolerance is defined on the basis ofthe scoring of SHAY and LAMBLING. The severity of the irritated areasand of the points of ulceration is scored from 0 to 3. An index ofulceration U and an index of hyperemia or irritation H are defined.##EQU1## Overall index of propensity for attack G=3U+H.

This index G is equal to 1 for the products of the invention, 12 for thecontrol and 74 for aspirin.

EXAMPLE 30: TEST OF BINDING TO RECEPTORS

A study of the binding of the compounds of the invention to differentcategories of receptors was carried out according to conventionaltechniques. It is apparent that some compounds of the invention bindwith good affinity (10⁻⁷ M) to MI muscarinic receptors, which does notappear to have been reported hitherto for comparable structures.

EXAMPLE 31: PHARMACEUTICAL COMPOSITION: TABLET

Tablets containing 25 mg of3-(2-piperidinoethyl)-3H-oxazolo[4,5-b]pyridin-2-one

    ______________________________________                                        Preparation formula for 1,000 tablets                                         ______________________________________                                        3-[2-(1-Pyrrolidinyl)ethyl]-3H-oxazolo-                                                               25 g                                                  [4,5-b]pyridin-2-one                                                          Wheat starch            15 g                                                  Corn starch             15 g                                                  Lactose                 65 g                                                  Magnesium stearate       1 g                                                  Silica                   1 g                                                  Hydroxypropoylcellulose  2 g                                                  ______________________________________                                    

APPENDIX Nomenclature

We claim:
 1. A compound selected from those of Formula (I)in which: R₁and R₂, with the nitrogen and oxygen to which connected, forman--O--CO--N link, W represents a halogen atom, or a lower alkyl oralkoxy group optionally substituted with one or more halogen atoms, mbeing 0 to 3, inclusive, A is a linear or branched alkyl radical having1 to 6 carbon atoms, inclusive, R₃ and R₄, which may be identical ordifferent, represent:a hydrogen atom, a linear or branched lower alkylgroup, a linear or branched lower alkenyl group, a cycloalkyl grouphaving 6 to 10 carbon atoms, inclusive, an aryl or (lower alkyl)arylgroup,each of these groups being optionally substituted with one or morehalogen atoms or with a trifluoromethyl, hydroxyl, or lower alkoxygroup, or alternatively: R₃ and R₄, with the nitrogen atom to which theyare linked, constitute a saturated or unsaturated, mono- or bicyclicnitrogenous heterocyclic system having at most 12 atoms--not countingthe hydrogen atoms--among which may be included one to three heteroatoms selected from nitrogen, oxygen and sulfur, unsubstituted orsubstituted with lower alkyl, phenyl, phenyl(lower alkyl), ordiphenyl(lower alkyl) it being possible for the phenyl, phenyl(loweralkyl), or diphenyl(lower alkyl) group to be substituted with one ormore halogen atoms or a hydroxyl, lower alkyl, lower alkoxy, ortrifluoromethyl group, on condition that R₃ and R₄, with the nitrogenatom to which they are linked, do not constitute a 4-arylpiperazinesystem, the terms lower alkyl, lower alkenyl, and lower alkoxy beingunderstood to mean a linear or branched group having 1 to 6 carbonatoms, inclusive, and aryl being understood to mean an unsaturated mono-or bicyclic group having 5 to 12 carbon atoms, inclusive, its isomers,epimers and diastereoisomers, as well as its addition salts with apharmaceutically-acceptable acid, provided however that, when mrepresents zero and A represents --CH₂ -- or when m represents one and Wrepresents halogen, then R₃ and R₄ with the nitrogen atom to which theyare linked, constitute a saturated or unsaturated, mono- or bicyclicnitrogenous heterocyclic system having at most 12 atoms--not countingthe hydrogen atoms-- among which may be included one to three heteroatoms selected from nitrogen, oxygen and sulfur, unsubstituted orsubstituted with a lower alkyl, phenyl, phenyl(lower alkyl), ordiphenyl(lower alkyl) it being possible for the phenyl, phenyl(loweralkyl), or diphenyl(lower alkyl) group to be substituted with one ormore halogen atoms or a hydroxyl, lower alkyl, lower alkoxy, ortrifluoromethyl group, on condition that R₃ and R₄, with the nitrogenatom to which they are linked, do not constitute a 4-arylpiperazinesystem.
 2. A compound as claimed in claim 1 selected from those in whichR₁ and R₂ together form a CO group, of formula (I/A): ##STR13## as wellas its addition salts with a pharmaceutically acceptable acid.
 3. Acompound as claimed in claim 1 selected from those in which R₃ and R₄,with the nitrogen atom which bears them, represent a saturated mono- orbicyclic nitrogenous heterocyclic system having 5 to 12 atoms notcounting the hydrogen atoms optionally incorporating in its carbonskeleton 1, 2 or 3 hetero atoms selected from nitrogen, oxygen, andsulfur, its isomers, epimers and diastereoisomers, as well as itsaddition salts with a pharmaceutically acceptable acid.
 4. The compoundas claimed in claim 1 which is selected from3-(2-piperidinoethyl)-3H-oxazolo[4,5-b]pyridin-2-one, as well as itsaddition salts with a pharmaceutically acceptable acid.
 5. The compoundas claimed in claim 1 which is selected from3-[2-(4-methyl-1-piperazinyl)ethyl]-3H-oxazolo[4,5-b]pyridin-2-one, aswell as its addition salts with a pharmaceutically acceptable acid. 6.The compound as claimed in claim 1 which selected from3-[2-(1-pyrrolidinyl)ethyl]-3H-oxazolo[4,5-b]pyridin-2-one, as well asits addition salts with a pharmaceutically acceptable acid.
 7. Thecompound as claimed in claim 1 which is selected from3-(2-morpholinoethyl)-3H-oxazolo[4,5-b]pyridin-2-one, as well as itsaddition salts with a pharmaceutically acceptable acid.
 8. Apharmaceutical composition useful for treating cerebral circulatoryinsufficiency containing as active principle a compound selected fromthose of Formula (I) ##STR14## in which: R₁ and R₂, with the nitrogenand oxygen to which connected, form an--O--CO--N link, W represents ahalogen atom or a lower alkyl or alkoxy group optionally substitutedwith one or more halogen atoms, m being 0 to 3, inclusive, A is a linearor branched alkyl radical having 1 to 6 carbon atoms, inclusive, R₃ andR₄, which may be identical or different, represent:a hydrogen atom, alinear or branched lower alkyl group, a linear or branched lower alkenylgroup, a cycloalkyl group having 6 to 10 carbon atoms, inclusive, anaryl or (lower alkyl)aryl group,each of these groups being optionallysubstituted with one or more halogen atoms or with a trifluoromethyl,hydroxyl, or lower alkoxy group, or alternatively: R₃ and R₄, with thenitrogen atom to which they are linked, constitute a saturated orunsaturated, mono- or bicyclic nitrogenous heterocyclic system having atmost 12 atoms--not counting the hydrogen atoms--among which may beincluded one to three hetero atoms selected from nitrogen, oxygen andsulfur, unsubstituted or substituted with lower alkyl, phenyl,phenyl(lower alkyl), or diphenyl(lower alkyl), it being possible for thephenyl, phenyl(lower alkyl), or diphenyl(lower alkyl) group to besubstituted with one or more halogen atoms or a hydroxyl, lower alkyl,lower alkoxy, or trifluoromethyl group, on condition that R₃ and R₄,with the nitrogen atom to which they are linked, do not constitute a4-arylpiperazine system, the terms lower alkyl, lower alkenyl, and loweralkoxy being understood to mean a linear or branched group having 1 to 6carbon atoms, inclusive, and aryl groups being understood to mean anunsaturated mono- or bicyclic group having 5 to 12 carbon atoms,inclusive, its isomers, epimers and diastereoisomers, as well as itsaddition salts with a pharmaceutically-acceptable acid, in combinationwith a pharmaceutically-acceptable excipient or vehicle.
 9. Amethod-of-treating a living animal afflicted with a disorder of cerebralcirculatory insufficiency comprising the step of administering to thesaid living animal an amount of a compound selected from those ofFormula (I) ##STR15## in which: R₁ and R₂, with the nitrogen and oxygento which connected, form an--O--CO--N link, W represents a halogen atomor a lower alkyl or alkoxy group optionally substituted with one or morehalogen atoms, m being 0 to 3, inclusive, A is a linear or branchedalkyl radical having 1 to 6 carbon atoms, inclusive, R₃ and R₄, whichmay be identical or different, represent:a hydrogen atom, a linear orbranched lower alkyl group, a linear or branched lower alkenyl group, acycloalkyl group having 6 to 10 carbon atoms, inclusive, an aryl or(lower alkyl)aryl group,each of these groups being optionallysubstituted with one or more halogen atoms or with a trifluoromethyl,hydroxyl, or lower alkoxy group, or alternatively: R₃ and R₄, with thenitrogen atom to which they are linked, constitute a saturated orunsaturated, mono- or bicyclic nitrogenous heterocyclic system having atmost 12 atoms--not counting the hydrogen atoms--among which may beincluded one to three hetero atoms selected from nitrogen, oxygen andsulfur, unsubstituted or substituted with lower alkyl, phenyl,phenyl(lower alkyl), or diphenyl(lower alkyl), it being possible for thephenyl, phenyl(lower alkyl), or diphenyl(lower alkyl) group to besubstituted with one or more halogen atoms or a hydroxyl, lower alkyl,lower alkoxy, or trifluoromethyl group, on condition that R₃ and R₄,with the nitrogen atom to which they are linked, do not constitute a4-arylpiperazine system, the terms lower alkyl, lower alkenyl, and loweralkoxy being understood to mean a linear or branched group having 1 to 6carbon atoms, inclusive, and aryl groups being understood to mean anunsaturated mono- or bicyclic group having 5 to 12 carbon atoms,inclusive, its isomers, epimers and diastereoisomers, as well as itsaddition salts with a pharmaceutically-acceptable acid, which iseffective for alleviation of said condition.
 10. A compound of claim 1wherein W represents a trifluoromethyl group.
 11. A pharmaceuticalcomposition of claim 8 wherein W represents a trifluoromethyl group. 12.A method of claim 9 wherein W represents a trifluoromethyl group.
 13. Apharmaceutical composition of claim 8 wherein the compound is3-[2-(1-pyrrolidinyl)ethyl]-3H-oxazolo[4,5-b]pyridin-2-one or apharmaceutically-acceptable acid addition salt thereof.
 14. A method ofclaim 9 wherein the compound is3-[2-(1-pyrrolidinyl)ethyl]-3H-oxazolo[4,5-b]pyridin-2-one or apharmaceutically-acceptable acid addition salt thereof.